Technical Field
The present invention relates generally to p97-antibody conjugates, related compositions and methods of using the same. Certain embodiments are more specifically directed to conjugates comprising a p97 polypeptide sequence and an antibody or antigen-binding fragment thereof that specifically binds to a cell surface receptor or cell surface protein, or a cancer-associated antigen, such as the human Her2/neu protein or the Her1/EGF receptor. Such antibody conjugates are useful, for example, in methods for treating a variety of diseases, including oncological diseases such as Her2/neu-expressing and Her1/EGFR-expressing cancers.
Description of the Related Art
Overcoming the difficulties of delivering therapeutic agents to specific regions of the brain represents a major challenge to treatment of most brain disorders. In its neuroprotective role, the blood-brain barrier (BBB) functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts. It is reported that over 95% of all therapeutic molecules do not cross the blood-brain barrier.
Trastuzumab (tradename Herceptin®), an approved monoclonal antibody specific for the human Her2/neu protein, is an important therapeutic option in the treatment of the approximately 30% of human breast cancers that are positive for this protein. While trastuzumab has proven valuable in the treatment and control of systemic disease; it cannot address the frequently observed spread of metastatic Her2/neu-expressing cancer cells in the central nervous system (CNS), due to the fact that trastuzumab cannot cross the blood-brain barrier.
There is an important unmet need for improving the therapeutic potential of antibodies, including those that are specific for Her2/neu or Her1/EGFR. For example, there is a need for anti-Her2/neu or anti-Her1/EGFR antibodies and antigen-binding fragments that have improved activity and/or other properties relative to conventional antibodies. In addition, there is a need for compositions and methods that facilitate the delivery of anti-Her2/neu or anti-Her1/EGFR antibodies across the blood-brain-barrier in order to effectively treat Her2/neu+ or Her1/EGFR+ cancers, particularly those that have metastasized to the CNS. These same needs apply to other cancer antigen-specific antibodies, including antibodies that are specific for Her3, A33 antigen, CD5, CD19, CD20, CD22, CD23 (IgE Receptor), C242 antigen, 5T4, IL-6, IL-13, vascular endothelial growth factor VEGF (e.g., VEGF-A), and others.
The present invention addresses these needs and offers other related advantages.